Summary. Syndecan-1 is a cell membrane proteoglycan that binds extracellular matrix components and various growth factors. It is expressed only on malignant plasma cells in bone marrow samples from patients with multiple myeloma (MM). Several reports have suggested that syndecan-1 was present only on a part of the myeloma cells. By using either IL-6-dependent myeloma cell lines or primary myeloma cells stained by annexin V, we report here that syndecan-1 was rapidly lost by myeloma cells undergoing apoptosis. In the same experimental conditions, expression of other cell membrane antigens such as CD38, HLA class-I or CD49d on apoptotic myeloma cells was not affected. In addition, we show that syndecan-1 loss was independent of activation of the gp130 IL-6 transducer. Dexamethasone induced a strong apoptosis of myeloma cells associated with the loss of syndecan-1. Finally, by using freshly-explanted tumoural samples, we show that syndecan-1 rapidly disappeared from myeloma cells in association with induction of apoptosis. In conclusion we showed that syndecan-1 is a marker for viable myeloma cells which is rapidly lost by apoptotic cells. These results emphasize the usefulness of anti-syndecan-1 antibodies to purge tumoural cells from haemopoietic grafts or to purify these cells for further manipulations for immuno or gene therapies.
Induction of apoptosis is a function of both an external stimulus and the physiology of the cell, which includes the expression of multiple oncogenes and tumor suppressors. Here we have studied the apoptotic response of immortalized mouse fibroblasts to serum withdrawal. We show that, in addition to the p53‐independent apoptosis observed in p53‐ cells, overexpression of wild‐type p53 tumor suppressor results in a high rate of programmed cell death. However, physiological range, low levels of the p53 protein protect fibroblasts from induction of apoptosis. Our results indicate that, as a function of its dose, the wild‐type p53 can either protect from death or promote apoptosis. This new, anti‐apoptotic, activity of p53 may have implications for the understanding of the role played by p53 in embryonic development as well as in initial stages of oncogenesis.
Multiple myeloma (MM) is a B‐cell neoplasia that is associated with an increased level of bone resorption. One important mediator of bone remodelling, insulin‐like growth factor (IGF‐I), has been shown to stimulate the proliferation of human myeloma cells. However, the mechanisms of action of IGF‐I in these cells have not been determined. Using interleukin (IL)‐6‐dependent myeloma cell lines, we show IGF‐I to be as potent a survival and proliferation factor as IL‐6. We demonstrated that IGF‐I functions independently of the IL‐6 transducer gp130 and that these two cytokines have additive effects. Moreover, inhibition of the IGF‐I pathway did not modulate the proliferative effect of IL‐6. Accordingly, we found that IL‐6 and IGF‐I activated distinct downstream signalling molecules: IL‐6 activated STAT3 phosphorylation, whereas IGF‐I treatment resulted in the phosphorylation of IRS‐1. Interestingly, these signalling pathways appear to converge as both cytokines activated the ras/MAPK pathway. Thus, IGF‐I acts as a potent survival and proliferation factor for myeloma cells by stimulating an IL‐6‐independent signalling cascade. These data, together with the finding that, in vivo, IGF‐I is normally expressed in close proximity to myeloma cells within the bone matrix, strongly suggest a role for this cytokine in the pathophysiology of multiple myeloma.
Multiple myeloma (MM) is a B-cell neoplasia that is associated with an increased level of bone resorption. One important mediator of bone remodelling, insulin-like growth factor (IGF-I), has been shown to stimulate the proliferation of human myeloma cells. However, the mechanisms of action of IGF-I in these cells have not been determined. Using interleukin (IL)-6-dependent myeloma cell lines, we show IGF-I to be as potent a survival and proliferation factor as IL-6. We demonstrated that IGF-I functions independently of the IL-6 transducer gp130 and that these two cytokines have additive effects. Moreover, inhibition of the IGF-I pathway did not modulate the proliferative effect of IL-6. Accordingly, we found that IL-6 and IGF-I activated distinct downstream signalling molecules: IL-6 activated STAT3 phosphorylation, whereas IGF-I treatment resulted in the phosphorylation of IRS-1. Interestingly, these signalling pathways appear to converge as both cytokines activated the ras/MAPK pathway. Thus, IGF-I acts as a potent survival and proliferation factor for myeloma cells by stimulating an IL-6-independent signalling cascade. These data, together with the finding that, in vivo, IGF-I is normally expressed in close proximity to myeloma cells within the bone matrix, strongly suggest a role for this cytokine in the pathophysiology of multiple myeloma.
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